New MTX-531 Research in Nature Cancer Highlights Promising Dual Inhibitor Strategy for Overcoming Cancer Resistance

MTX-531在自然癌症中的新研究突出了克服癌症耐药性的有前途的双重抑制剂策略

MINNEAPOLIS, July 11, 2024 /PRNewswire/ -- MEKanistic Therapeutics Inc., a biotechnology company pioneering the development of next-generation kinase inhibitors for cancer treatment, today announced the peer-reviewed publication of new preclinical research on its lead candidate, MTX-531, an investigational dual-targeting therapy, in Nature Cancer.

明尼阿波利斯，2024年7月11日/PRNewswire/--Mekanitic Therapeutics Inc.，一家开创下一代激酶抑制剂癌症治疗开发的生物技术公司，今天宣布了对其主要候选药物MTX-531（一种研究性双靶向治疗）在Nature cancer的新临床前研究的同行评审出版物。

MTX-531 is a potential first-in-class therapy uniquely designed to inhibit both EGFR (Epidermal Growth Factor Receptor) and PI3K (Phosphoinositide 3-kinase), two critical proteins involved in cancer cell survival and proliferation..

MTX-531是一种潜在的一流疗法，独特设计用于抑制EGFR（表皮生长因子受体）和PI3K（磷酸肌醇3-激酶），这是两种参与癌细胞存活和增殖的关键蛋白。。

'We are excited to share the positive MTX-531 preclinical research published in Nature Cancer, which we believe show promising signals toward a novel solution to addressing the root cause of resistance to current cancer treatments,' said Danny Cunagin, chief executive officer, MEKanistic Therapeutics.

Mekanitic Therapeutics首席执行官丹尼·库纳金（Danny Cunagin）说：“我们很高兴分享发表在《自然癌症》（Nature Cancer）上的MTX-531阳性临床前研究，我们认为这显示出有希望的信号，可以找到一种新的解决方案来解决目前癌症治疗耐药的根本原因。”。

'By targeting critical adaptive resistance mechanisms with a dual inhibition strategy, we aim to significantly halt cancer progression compared to single-target treatments, and look forward to advancing this innovative therapy to patients in clinical trials.'.

“通过采用双重抑制策略靶向关键的适应性耐药机制，我们的目标是与单靶点治疗相比显着阻止癌症进展，并期待在临床试验中向患者推进这种创新疗法。”。

Key Findings of MTX-531 Study

MTX-531研究的主要发现

High Potency, Selectivity Leading to First of Its Kind Tolerability

高效力，选择性导致同类耐受性首创

Preclinical studies demonstrated that MTX-531 exhibits nanomolar potency against both EGFR and PI3K (14.7 nM for EGFR, 6.44 nM for PI3K), with a high degree of selectivity as determined by broad kinome testing. In addition, MTX-531 did not cause hyperglycemia in mice at therapeutic doses, unlike other known pan-PI3K inhibitors, which have been reported to significantly increase blood glucose and insulin levels both in preclinical and clinical settings. .

临床前研究表明，MTX-531对EGFR和PI3K均表现出纳摩尔效力（EGFR为14.7 nM，PI3K为6.44 nM），通过广泛的激酶组测试确定具有高度选择性。此外，与其他已知的泛PI3K抑制剂不同，MTX-531在治疗剂量下不会引起小鼠高血糖，据报道，其他已知的泛PI3K抑制剂在临床前和临床环境中均能显着增加血糖和胰岛素水平。。

Judith Sebolt-Leopold, PhD, chief scientific officer, MEKanistic Therapeutics, commented, 'MTX-531 is the first PI3K inhibitor capable of selectively co-targeting EGFR and the first known pan-PI3K inhibitor that does not induce hyperglycemia, a known challenge with PI3K inhibitors that often leads to treatment discontinuation.

Mekanitic Therapeutics首席科学官Judith Sebolt Leopold博士评论道：“MTX-531是第一种能够选择性共靶向EGFR的PI3K抑制剂，也是第一种已知的不诱导高血糖的泛PI3K抑制剂，这是PI3K抑制剂的已知挑战，常会导致治疗中断。

This unique feature, achieved through precise targeting enabled by MTX-531's computational design, confers a favorable therapeutic index and resilience to adaptive resistance mechanisms not observed in prior PI3K inhibitor clinical programs.'.

通过MTX-531的计算设计实现的精确靶向实现的这一独特功能，赋予了有利的治疗指数和对先前PI3K抑制剂临床程序中未观察到的适应性耐药机制的恢复能力。”。

Robust Tumor Suppression as Monotherapy and in Combination Therapy

作为单一疗法和联合疗法的强大肿瘤抑制

MTX-531 monotherapy led to significant tumor regression in preclinical models of head and neck squamous cell carcinoma (HNSCC). Oral therapy effectively inhibited PI3K and EGFR signaling in a balanced fashion, achieving objective responses in every HNSCC model evaluated. Complete tumor regressions were observed across a broad dose range, with survival improvement ranging from 62% to >500% across models..

MTX-531单一疗法在头颈部鳞状细胞癌（HNSCC）的临床前模型中导致显着的肿瘤消退。口服治疗以平衡的方式有效抑制PI3K和EGFR信号传导，在每个评估的HNSCC模型中实现客观反应。在广泛的剂量范围内观察到完全的肿瘤消退，各模型的生存率从62%提高到>500%。。

In addition, when combined with a MEK inhibitor (trametinib) or a KRAS inhibitor (sotorasib), treatment with MTX-531 more than doubled the incidence of tumor regressions achieving a 100% objective response rate in multiple KRAS mutant colorectal (CRC) and pancreatic tumor models.

此外，当与MEK抑制剂（曲美替尼）或KRAS抑制剂（索托拉西布）联合使用时，MTX-531治疗使肿瘤消退的发生率增加了一倍以上，在多个KRAS突变结直肠（CRC）和胰腺肿瘤模型中达到100%的客观缓解率。

Dr. Sebolt-Leopold added, 'Our collective preclinical data show that MTX-531 effectively inhibits tumor growth in cancers with PIK3CA and KRAS mutations, which often lead to aggressive behavior and resistance to standard therapies. MTX-531 was well tolerated and outperformed the combination of drugs that individually target EGFR and PI3K.

Sebolt Leopold博士补充道，“我们的集体临床前数据显示，MTX-531有效抑制PIK3CA和KRAS突变癌症的肿瘤生长，这通常会导致攻击性行为和对标准疗法的抵抗。MTX-531耐受性良好，优于单独靶向EGFR和PI3K的药物组合。

These findings highlight the versatility and broader potential of MTX-531 in treating hard-to-treat cancers.'.

这些发现突出了MTX-531在治疗难治性癌症方面的多功能性和更广泛的潜力。

The scientific paper can be accessed at the following link: https://www.nature.com/articles/s43018-024-00781-6

可以通过以下链接访问科学论文：https://www.nature.com/articles/s43018-024-00781-6

About MTX-531 Development

关于MTX-531的发展

Investigational new drug-enabling toxicology studies sponsored by the National Cancer Institute's Experimental Therapeutics (NExT) Program are currently underway. The NExT Program aims to advance clinical practice by supporting promising new drug discovery and development projects. Through this program, MEKanistic Therapeutics collaborates with NCI staff and contractors on a milestone-driven project team to conduct these studies and assess MTX-531's safety and efficacy in patients with cancer..

由国家癌症研究所实验疗法（NExT）计划赞助的研究性新药毒理学研究目前正在进行中。下一个项目旨在通过支持有前途的新药发现和开发项目来推进临床实践。通过这个项目，Mekanitic Therapeutics与NCI员工和承包商合作，组建了一个里程碑驱动的项目团队，进行这些研究，并评估MTX-531在癌症患者中的安全性和有效性。。

'Our partnership with the NCI is a testament to the promising potential of MTX-531,' said Christopher Whitehead, PhD, co-founder and chief operating officer, MEKanistic Therapeutics. 'With their support and our focused efforts on GMP manufacturing and drug product development, we are poised to make significant strides in bringing this innovative therapy closer to clinical trials and ultimately to patients in need.'.

Mekanitic Therapeutics联合创始人兼首席运营官克里斯托弗·怀特黑德（ChristopherWhitehead）博士说：“我们与NCI的合作证明了MTX-531的巨大潜力。”在他们的支持和我们专注于GMP制造和药品开发的努力下，我们准备在使这种创新疗法更接近临床试验并最终接近需要的患者方面取得重大进展。”。

About MEKanistic Therapeutics, Inc.

关于Mekanitic Therapeutics，Inc。

MEKanistic Therapeutics Inc. is a privately held, Minneapolis, MN based biotechnology company focused on developing innovative kinase inhibitors for the treatment of cancer. The company studies the landscape of signal transduction pathways to create more effective cancer treatments. By targeting compensatory signaling in response to pathway intervention, MEKanistic designs drugs that prevent tumors from developing resistance to targeted therapies.

Mekanitic Therapeutics Inc.是一家位于明尼苏达州明尼阿波利斯的私营生物技术公司，专注于开发用于治疗癌症的创新激酶抑制剂。该公司研究信号转导途径的前景，以创造更有效的癌症治疗方法。通过针对途径干预的补偿性信号传导，Mekanic设计了防止肿瘤对靶向治疗产生耐药性的药物。

The company's lead candidate is MTX-531, a single molecule that was rationally designed to selectively block two key pathways (EGFR and PI3K) that promote tumor progression. For more information, visit mekanistic.com and engage with MEKanistic on LinkedIn..

该公司的主要候选药物是MTX-531，这是一种合理设计的单分子，可选择性阻断促进肿瘤进展的两个关键途径（EGFR和PI3K）。有关更多信息，请访问mekanitic.com并在LinkedIn上与mekanitic互动。。

Media Contact: Priyanka Shah priyanka@bioscribe.com

媒体联系人：Priyanka Shahpriyanka@bioscribe.com

Forward-Looking Statements

前瞻性声明

This press release may contain 'forward-looking statements' within the meaning of the federal securities laws, which involve risks and uncertainties including statements regarding the potential benefits, safety, and efficacy of MTX-531, and which can be identified by the use of forward-looking terminology such as 'may,' 'will,' 'expect,' 'plan,' 'anticipate,' 'believe,' 'estimate,' or 'continue' or the negative thereof or other variations thereon or comparable terminology.

本新闻稿可能包含《联邦证券法》所指的“前瞻性声明”，其中涉及风险和不确定性，包括有关MTX-531潜在益处、安全性和有效性的声明，并且可以通过使用前瞻性术语来识别，例如“可能”、“将”、“预期”、“计划”、“预期”、“相信”、“估计”或“继续”或其负面或其他变化或类似术语。

MEKanistic Therapeutics Inc. has based these forward-looking statements on its current expectations and forecasts about future events. Actual results could differ materially from those projected in such forward-looking statements due to a number of factors..

Mekanitic Therapeutics Inc.根据其目前对未来事件的预期和预测，做出了这些前瞻性陈述。由于许多因素，实际结果可能与此类前瞻性声明中预测的结果存在重大差异。。

SOURCE MEKanistic Therapeutics, Inc.

来源Mekanitic Therapeutics，Inc。